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Garlic Metabolism and Cytochrome P450 Modulation

大蒜代谢和细胞色素 P450 调节

基本信息

批准号：
7228080
负责人：
DANNY D SHEN
金额：
$ 20.62万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7228080
关键词：
ABCB1 gene Acute Affect Alprazolam American Animals Anticoagulants Area Attention Blood Bupropion CYP2E1 gene CYP3A4 gene Caffeine Case Study Chlorzoxazone Cholesterol Chronic Class Classification Clinical Clinical Research Collection Comparative Study Conflict (Psychology)Cytochrome P450 Daily Data Digoxin Documentation Drug Interactions Drug Kinetics Enzymes Garlic Garlic Extract HIV Protease Inhibitors HIV-1 Health Professional Hepatic Herb Herb-Drug Interactions Herbal Medicine Human Human Volunteers Hydrolysis In Vitro Intake Intestinal Mucosa Intestines Lead Lipids Literature Liver Marketing Measures Membrane Transport Proteins Metabolic Metabolic Biotransformation Metabolism Metoprolol Midazolam Mus Numbers Omeprazole Oral P-Glycoprotein Patients Peptides Personal Satisfaction Pharmaceutical Preparations Phase Plasma Powder dose form Preparation Protease Inhibitor Protein Isoforms Rattus Recombinants Regulation Reporting Research Research Personnel Ritonavir Safety Sampling Saquinavir Sorting - Cell Movement Steam Sulfides Therapeutic Thinking Time Tolbutamide Treatment Protocols Universities Urine Variant Warfarin Washington absorption aged allicin allyl sulfide clinically significant cytochrome P450 3A design follow-up healthy volunteer human CYP2C9 protein human study human subject in vivo metabolic abnormality assessment programs treatment duration

项目摘要

DESCRIPTION (provided by applicant): Garlic supplements are widely used for the treatment of high blood cholesterol and lipids. Until recently, garlic supplements were thought to be well tolerated and relatively safe. Adverse interactions between garlic supplements and several narrow therapeutic drugs, including anticoagulants (warfarin, fuindione) and HIV protease inhibitors (saquinavir, ritonavir), have been reported within the past 2 years. Animal and in vitro studies with known organosulfur constituents of garlic, as well as garlic extracts, are known to simultaneously inhibit and induce several CYP enzymes (1A, 2B, 2C, 2E and 3A subfamilies) in the liver, as well as the efflux transporter P-gylcoproptein (Pgp) in the intestinal mucosa. However, very recent studies in human subjects have produced conflicting data as to the effects of garlic supplements on cytochrome P450 function. Our specific hypotheses are: 1) the effects of garlic supplements on CYP and Pgp function vary with the type of garlic preparation (viz. garlic powder, steamed-distilled garlic oil, and aged garlic); and 2) garlic's effect is time- and regimen-dependent (e.g. it acutely inhibits and chronically induces CYP3A4 and Pgp activities in human subjects). Two separate "cocktails" of CYP and Pgp probe substrates, including caffeine (1A2), buproprion (2B6), chlorzoxazone (2E1), tolbutamide (2C9), omeprazole (2C19), metoprolol (2D6), midazolam (3A4/5), and digoxin (Pgp), will be administered to a panel of healthy human volunteers at various times during and shortly after discontinuation of daily intake of garlic supplement. Pharmacokinetics of known bioactive garlic constituents and their biotransformation products will be simultaneously studied through collection of blood, breath and urine samples. Garlic metabolite data may offer clues as to which garlic-derived compounds may be responsible for the putative metabolic effects. Specifically, we will measure metabolites deriving from allicin and allylic sulfides, which are the main constituents of garlic powder and garlic oil. We will also measure metabolites of S-allylcysteine, which is derived from hydrolysis of allylic cysteinyl peptides in garlic powder and aged garlic. These metabolic studies in human subjects will be conducted at the University of Washington General Clinical Research Center. The results will provide critical information for the design of further clinical studies to characterize and elucidate potentially important adverse garlic-drug interactions.

描述(申请人提供)：大蒜补充剂被广泛用于治疗高血脂和高胆固醇。直到最近，大蒜补充剂还被认为耐受性好，而且相对安全。在过去的两年里，大蒜补充剂与几种狭窄的治疗药物，包括抗凝剂(华法林、呋喃二酮)和艾滋病毒蛋白酶抑制剂(沙奎那韦、利托那韦)之间的不良相互作用已有报道。已知的大蒜有机硫成分以及大蒜提取物在动物和体外研究中同时抑制和诱导肝脏中的几种CYP酶(1A、2B、2C、2E和3A亚家族)以及肠粘膜中的外流转运蛋白P-糖蛋白(PGP)。然而，关于大蒜补充剂对细胞色素P450功能的影响，最近在人类受试者中的研究产生了相互矛盾的数据。我们的具体假设是：1)大蒜补充剂对CYP和PGP功能的影响因大蒜制剂的类型而异。2)大蒜的作用具有时间和剂量依赖性(例如，它能强烈地抑制和慢性诱导人体内的细胞色素P3A4和Pgp活性)。两种不同的CYP和PGP探针底物，包括咖啡因(1A2)、布维酮(2B6)、氯唑沙宗(2E1)、甲苯丁胺(2C9)、奥美拉唑(2C19)、美托洛尔(2D6)、咪达唑仑(3A4/5)和地高辛(PGP)，将在停止每日大蒜补充剂摄入期间和之后不久的不同时间被给予一组健康的人类志愿者。已知的生物活性大蒜成分及其生物转化产物的药代动力学将通过采集血液、呼吸和尿样同时进行研究。大蒜代谢物的数据可能会提供线索，说明哪些大蒜衍生化合物可能对假定的代谢影响负责。具体地说，我们将测量大蒜素和大蒜硫化物的代谢物，这两种物质是大蒜粉和大蒜油的主要成分。我们还将测定大蒜粉和陈化大蒜中烯丙基半胱氨酸的代谢物S-烯丙基半胱氨酸的代谢产物。这些人体代谢研究将在华盛顿大学综合临床研究中心进行。这些结果将为设计进一步的临床研究提供关键信息，以表征和阐明潜在的重要的大蒜与药物的不良相互作用。